The prefrontal cortex (PFC) governs the integration of temporal and spatial factors that guide complex behaviors. The mesocortical dopaminergic system is vital for proper functioning of this region and dysfunction of this pathway has been implicated in the pathophysiology of schizophrenia and other mental disorders. Physiological and pharmacological studies suggest a number of synaptic and nonsynaptic mechanisms through which dopamine mediates its crucial modulatory role. The long-term objective of this proposal is to determine the cellular substrates for dopamine's physiological actions using electron microscopic immunocytochemical and neurophysiological methods. These studies will be performed in rats, since a considerable framework of functional studies regarding the mesocortical dopaminergic pathway has been established in this species. In Study I, dual labeling electron microscopic immunocytochemistry and tract-tracing will be used to determine whether there are (1) direct structural bases for postsynaptic regulation of GABAergic PFC neurons by dopaminergic terminals, (2) dendritic convergence of dopaminergic terminals with identified GABAergic or hippocampal terminals, and (3) axo-axonal associations between these terminals. In Study II, in vivo intracellular recordings will be combined with anatomical methods to (1) investigate the cellular bases for modulatory actions involving dopaminergic and hippocampal afferents to the PFC and (2) provide stained cells with characterized physiology for correlation with morphological, synaptic and immunocytochemical measurements. In Study III, an antiserum raised against a dopamine D2 receptor peptide will provide the first ultrastructural immunocytochemical localization of D2 receptor-like immunoreactivity (D2-LI) in the PFC and will be used to determine (1) the distribution of D2-LI along dendritic, axonal or glial membranes, (2) the relationship of D2-LI to dopaminergic terminals and (3) the relationship of D2-LI to GABAergic neurons and processes. The elucidation of the synaptic organization of the mesocortical dopaminergic system will improve understanding of its role in the cognitive, affective and motoric functions of the PFC and its contribution to the pathophysiology and treatment of psychiatric and neurological disorders.